Osteoporosis affects 20% of the female population over 65 years of age and there is an 80% excess mortality after an osteoporotic fracture. The preservation of bone mass as well as achieving a peak bone mass are fundamental to preventing this disease state. The risk of osteoporosis increases in women of low body weight or those who have a history of weight loss. In addition, recent studies have shown that in obese subjects, bone mineral density (BMD) decreases after moderate weight loss. Such findings are of particular concern due to the large number of American women (up to 40%) who are following a weight loss regimen. During weight reduction, the loss in lean body mass is dependent on the total caloric deficit and the protein intake. There is limited information about the loss of other proteins, such as collagen, which makes up approximately one third of the protein in the body and is primarily in bone. Collagen has a slow rate of turnover and therefore has generally been thought to be spared during semi- starvation. Our preliminary data, however, suggest the Opposite. We found that the rate of collagen cross-link excretion (as a measure of collagen turnover which represents bone resorption) doubles during a moderate weight loss regimen of about 1100 kcal/d. Moreover, the increased rate of bone resorption was greater in postmenopausal than premenopausal women. Subjects were counseled to consume about 800 mg of calcium/d, however their actual intake averaged about 500 mg/d. Thus, it is not clear whether calories and/or calcium might be responsible for the marked increased in bone resorption. The proposed investigation will explore the nutritional regulation of bone turnover during moderate weight reduction. Specifically, we will test the hypothesis that a low calcium intake during weight reduction accelerates the rate of bone turnover. Two recently developed measures of bone turnover, collagen cross-link excretion and serum osteocalcin levels, both of which are sensitive and specific for short-term studies, will be used to examine bone resorption and synthesis, respectively. We will determine whether the rate of weight loss, the absolute weight loss, or the level of calcium intake influence the rate of bone turnover and BMD. In addition, in order to address the mechanisms by which bone turnover is altered, the effect of weight loss and calcium intake on the hormonal regulators of bone turnover will be assessed. Complementary studies in a rat model will be used to further explore how nutritional parameters regulate bone composition, histology, and biomechanical properties. Importantly, these rodent studies will directly assess the relationship between biochemical and clinical indexes of bone health with the incidence of bone fractures. The long-term goals of this research program are to determine nutritional influences on cartilaginous tissues which can be applied in the prevention and treatment of osteoporosis.